Pomegranate derivative urolithin A enhances vitamin D receptor signaling to amplify serotonin-related gene induction by 1,25-dihydroxyvitamin D.
Pomegranate derivative urolithin A enhances vitamin D receptor signaling to amplify serotonin-related gene induction by 1,25-dihydroxyvitamin D.
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DOI：
10.1016/j.bbrep.2020.100825
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发表时间：
2020-12
影响因子：
2.7
通讯作者：
Jurutka PW
中科院分区：
文献类型：
--
作者：
Livingston S;Mallick S;Lucas DA;Sabir MS;Sabir ZL;Purdin H;Nidamanuri S;Haussler CA;Haussler MR;Jurutka PW
Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D), is known to regulate expression of genes impacting calcium and phosphorus metabolism, the immune system, and behavior. Urolithin A, a nutrient metabolite derived from pomegranate, possibly acting through AMP kinase (AMPK) signaling, supports respiratory muscle health in rodents and longevity in C. elegans by inducing oxidative damage-reversing genes and mitophagy. We show herein that urolithin A enhances transcriptional actions of 1,25D driven by co-transfected vitamin D responsive elements (VDREs), and dissection of this genomic effect in cell culture reveals: 1) urolithin A concentration-dependency, 2) occurrence with isolated natural VDREs, 3) nuclear receptor selectivity for VDR over ER, LXR and RXR, and 4) significant 3- to 13-fold urolithin A-augmentation of 1,25D-dependent mRNA encoding the widely expressed 1,25D-detoxification enzyme, CYP24A1, a benchmark vitamin D target gene. Relevant to potential behavioral effects of vitamin D, urolithin A elicits enhancement of 1,25D-dependent mRNA encoding tryptophan hydroxylase-2 (TPH2), the serotonergic neuron-expressed initial enzyme in tryptophan metabolism to serotonin. Employing quantitative real time-PCR, we demonstrate that TPH2 mRNA is induced 1.9-fold by 10 nM 1,25D treatment in culture of differentiated rat serotonergic raphe (RN46A-B14) cells, an effect magnified 2.5-fold via supplementation with 10 μM urolithin A. This potentiation of 1,25D-induced TPH2 mRNA by urolithin A is followed by a 3.1- to 3.7-fold increase in serotonin concentration in culture medium from the pertinent neuronal cell line, RN46A-B14. These results are consistent with the concept that two natural nutrient metabolites, urolithin A from pomegranate and 1,25D from sunlight/vitamin D, likely acting via AMPK and VDR, respectively, cooperate mechanistically to effect VDRE-mediated regulation of gene expression in neuroendocrine cells. Finally, gedunin, a neuroprotective natural product from Indian neem tree that impacts the brain derived neurotropic factor pathway, similarly potentiates 1,25D/VDR-action. Hormonal 1,25-dihydroxyvitamin D acts in brain to induce tryptophan hydroxylase-2. Urolithin A derived from ellagitannins in pomegranates curbs neuroinflammation. Urolithin A enhances the transcriptional actions of 1,25-dihydroxyvitamin D. Urolithin A raises 1,25-dihydroxyvitamin D-induced tryptophan hydroxylase-2 mRNA. Serotonin rises in raphe cells exposed to urolithin A and 1,25-dihydroxyvitamin D.
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影响因子：
5.9
作者：
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通讯作者：
Jurutka, Peter W.